Department of Biological Sciences (Regulatory Toxicology), National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India.
Department of Chemical Sciences, National Institute of Pharmaceutical Education and Research, Hyderabad, Telangana, India.
J Cell Physiol. 2022 May;237(5):2516-2527. doi: 10.1002/jcp.30717. Epub 2022 Mar 13.
Chronic kidney disease is one of the major health burdens affecting a considerable number of people worldwide. The aberrant regulation of lysyl oxidase (LOX) family of enzymes results in establishment of dense extracellular matrix (ECM). Since, LOX enzymes need copper (Cu) for their proper catalytic activity; the present study investigated the efficacy of a copper chelator, disulfiram (DSF) in renal fibrosis. Antifibrotic activity of DSF was investigated in kidney epithelial cells stimulated by transforming growth factor-β1 (5 ng/ml) as well as in two animal models. The renal injury was induced in animals by unilateral ureteral obstruction and folic acid administration (250 mg/kg). The DSF (3 and 10 mg/kg, every 3rd day) and standard LOX inhibitor, β-aminopropionitrile (BAPN, 100 mg/kg, daily) administration was started on day 0 and continued till the day of sacrifice. DSF was found to be a potent LOX/LOXL2 inhibitor to reduce crosslinking of collagen fibrils leading to reduction in the collagen deposition. In addition, the DSF was demonstrated to inhibit epithelial-mesenchymal transition in the tubular cells and fibrotic kidneys. Our results suggested that DSF, being a clinically available drug could be translated to clinics for its potent antifibrotic activity due to its inhibitory effect on LOX proteins.
慢性肾脏病是影响全球相当数量人群的主要健康负担之一。赖氨酰氧化酶（LOX）家族酶的异常调节导致细胞外基质（ECM）的密集形成。由于 LOX 酶需要铜（Cu）才能发挥其适当的催化活性；因此，本研究调查了铜螯合剂二硫化物（DSF）在肾纤维化中的疗效。通过转化生长因子-β1（5ng/ml）刺激的肾上皮细胞以及两种动物模型研究了 DSF 的抗纤维化活性。通过单侧输尿管梗阻和叶酸给药（250mg/kg）在动物中诱导肾损伤。DSF（3 和 10mg/kg，每 3 天一次）和标准 LOX 抑制剂β-氨基丙腈（BAPN，100mg/kg，每天）的给药于第 0 天开始，并持续到处死日。发现 DSF 是一种有效的 LOX/LOXL2 抑制剂，可减少胶原纤维原纤维的交联，从而减少胶原沉积。此外，DSF 被证明可抑制管状细胞和纤维化肾脏中的上皮-间充质转化。我们的研究结果表明，DSF 作为一种临床可用的药物，由于其对 LOX 蛋白的抑制作用，可能因其强大的抗纤维化活性而被转化为临床应用。
